A number of naturally occurring proteins have uninterrupted tracts of glutamine residues encoded by the CAG triplet repeats. It now known that the expansion of the length of these uninterrupted tracts or regions of trinucleotide repeats in proteins is associated with specific neurodegenerative diseases. The expansion of polyglutamine tracts in proteins may become pathogenic if the polyglutamine tracts expand beyond a threshold length, which for most of the polyglutamine expansion-associated disorders is a length of approximately 35–40 residues. When the threshold is reached, the presence of the abnormal protein is associated with neurodegenerative diseases such as: Huntington's disease, spinocerebellar ataxias (SCAs), spinobulbar muscular atrophy (SBMA, Kennedy disease), and dentatorubropallidoluysian atrophy (DRPLA). In each of these disorders, abnormal expanded regions of CAG repeats have been identified in the coding region of a protein.
Cellular and genetic characteristics of the polyglutamine expansion-associated disorders have begun to be elucidated. It is known that Huntington's disease is characterized by mutant huntingtin protein with abnormal expanses of polyglutamine tracts. In Spinocerebellar Ataxia Type 1 (SCA1), the ATX1 gene includes abnormal expanded CAG repeats and encodes a mutant ataxin-1 protein that contains abnormal polyglutamine stretches. A similar situation has been identified in Spinocerebellar Ataxia Type 2 (SCA2), which is characterized by abnormal expansion of CAG repeats located in the ATX2 gene. The abnormal ATX2 gene encodes mutant ataxin-2 that includes abnormal polyglutamine stretches. In spinocerebellar Ataxia Type 3 (SAC3), which is also known as Machado-Joseph disease (MJD), the mutant ATX3 gene includes abnormal numbers of CAG repeats and encodes mutant ataxin-3 protein with characteristic expanded polyglutamine stretches. Spinocerebellar Ataxia Type 7 (SCA7) is associated with an abnormal SCA7 gene that encodes mutant ataxin-7 protein with the expanded polyglutamine regions. In spinocerebellar ataxia Type 6 (SCA6) there are expanses of CAG repeats in the coding region of an isoform of the alpha-1A calcium channel subunit (CACNA1A), which are predicted to encode polyglutamine stretches in the protein. In spinobulbar muscular atrophy (SBMA), CAG repeats located in the androgen receptor gene result in abnormal polyglutamine stretches in the androgen receptor protein encoded by the gene. In DRPLA, the DRPLA gene exhibits abnormal CAG repeats and encodes mutant atropin-1 protein, which shows expanded polyglutamine stretches that are characteristic of the polyglutamine expansion-associated disorders.
Common features of polyglutamine expansion-associated diseases include the gradual loss of neurons with a concomitant loss of motor and cognitive functions, but there are clinical differences in the various diseases. For example, the onset of Huntington's disease is characterized by choreic movements that result from the selective involvement of medium spiny neurons of the striatum. In contrast, the onset of SBMA, which is an X-linked disease involving a polyglutamine tract in the androgen receptor protein (AR), is characterized by weakness and swallowing difficulties because motor neurons in the brain stem and spinal cord are selectively lost (H. L. Paulson, Brain Pathology 10:293–299, 2000). As each of the polyglutamine expansion-associated diseases progresses, more regions of the brain and spinal cord of the patient become involved.
The severity of the symptoms and progression of the polyglutamine expansion-associated diseases varies from patient to patient, in part due to fact that the length of the expanded polyglutamine region correlates with the severity of the symptomatic presentation. Thus, patients with longer expanded polyglutamine regions may have more severe clinical effects from the disease and may show an earlier age of onset than would patients with shorter expanded polyglutamine regions. Although there is some variation between the polyglutamine expansion-associated diseases, they all generally present symptomatically in mid to late life and all but SBMA, which is X-linked, are dominantly inherited.
The polyglutamine expansion-associated diseases are all neurodegenerative and fatal (R. E. Hughes & J. M. Olson, Nature Medicine, 7:419–423, 2001), and although it is possible to diagnose polyglutamine expansion-associated disorders such as Huntington's disease, there are very limited treatment options available for patients diagnosed with one of the disorders. The lack of effective treatments for polyglutamine expansion-associated disorders means that even with a definitive diagnosis, the therapeutic options are quite limited. Thus, there is a significant need for effective compounds and methods for preventing and/or treating polyglutamine expansion-associated disorders as well as a need for methods to identify candidate pharmaceutical agents useful to treat these devastating diseases.